This invention relates to a new class of chemical compounds which can be described generally as substituted 4-aminomethyl-3-pyridinols and to their non-toxic pharmaceutically acceptable acid addition salts.
Pharmacological studies indicate that the instant products are effective antihypertensive, diuretic and saluretic agents which can be used in the treatment of conditions associated with electrolyte and fluid retention and hypertension. When administered in a therapeutic dosage in conventional vehicles, the instant products effectively reduce the amount of sodium and chloride ions in the body, lower dangerous excesses of fluid to acceptable levels and, in general, alleviate conditions usually associated with edema and hypertension. Accordingly, their antihypertensive activity does not depend solely on their diuretic and saluretic properties.
The substituted 4-aminomethyl-3-pyridinols of this invention are compounds having the following structural formula: ##STR1## wherein X is chloro, bromo, iodo or hydrogen;
R is straight or branched chain lower alkyl wherein the alkyl group has up to 5 carbon atoms; PA1 X is chloro, bromo or iodo; PA1 R is straight or branched chain lower alkyl wherein the alkyl group has 2 to 4 carbon atoms; PA1 2-iodo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol; PA1 2-iodo-4-aminomethyl-6-(1-methylethyl)-3-pyridinol; PA1 2-bromo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol; PA1 2-chloro-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol; PA1 2-iodo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol dihydrochloride.
And the non-toxic pharmaceutically acceptable acid addition salts thereof.
A more preferred embodiment of this invention are those compounds of Formula I wherein
And the non-toxic pharmaceutically acceptable acid addition salts thereof.
The non-toxic pharmaceutically acceptable acid addition salts mentioned above are preferably the salts derived from non-toxic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, methanesulfonic acid, isethionic acid and the like.
Preferred specific compounds of this invention can be
The substituted 4-aminomethyl-3-pyridinols of this invention of Formula I can be prepared by the following synthetic method.
A N-acyl ester of glycine of the formula: ##STR2## wherein R is as previously defined and R.sub.1 is straight chain lower alkyl is dehydrated to give a substituted oxazole of the formula: ##STR3## wherein R and R.sub.1 are as previously defined which is then condensed with acrylonitrile to provide a substituted pyridine of the formula: ##STR4## wherein R is as previously defined which is hydrogenated in the presence of a suitable acid to give salts of the formula: ##STR5## wherein R is as previously defined and A is a pharmaceutically acceptable anion which, in turn, is halogenated and then neutralized with a suitable base to afford the compounds of this invention of Formula I. Treatment of the latter with a nontoxic pharmaceutically acceptable acid gives the corresponding acid addition salt of the formula ##STR6## wherein R, X and A are as defined previously. A detailed description of this method follows.
(1) A N-acyl ester of glycine of formula II wherein R is as previously defined and R.sub.1 is straight chain lower alkyl, preferably ethyl or methyl, is treated with a suitable dehydrating agent, preferably phosphorus pentoxide, in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran and the like, preferably methylene chloride, at a temperature ranging between 20.degree. C. and 100.degree. C., preferably at the reflux temperature of the solvent, under an inert atmosphere for a period of 2 to 24 hours, preferably 6 to 8 hours. The resulting reaction mixture is treated with aqueous alkali, preferably 20% sodium hydroxide, and the product oxazole of formula III wherein R and R.sub.1 are as previously defined is isolated by distillation. ##STR7##
(2) An intimate mixture of an oxazole of Formula III and acrylonitrile is heated at a temperature ranging between 40.degree. C. and 100.degree. C., preferably 70.degree.-75.degree. C., for a period of 6 to 48 hours, preferably 12 to 24 hours, to give a substituted pyridine of Formula IV wherein R is as previously defined. The product IV is isolated by either chromatographing the reaction mixture on silica gel or distillation. The latter purification procedure involves distillation of unreacted III from the reaction mixture leaving the product IV as the pot residue which is readily purified by crystallization from a suitable solvent such as aqueous methanol. ##STR8##
(3) Hydrogenation of a nitrile of Formula IV in a suitable solvent such as methanol, ethanol, ethyl acetate and the like, preferably ethanol, in the presence of a suitable acid, preferably hydrochloric acid, and a catalyst such as 10% palladium on charcoal in a Parr apparatus at room temperature and an initial pressure of 40-45 p.s.i. until the theoretical quantity of hydrogen is consumed affords the salt of Formula V wherein R and A are as previously defined after removal of the catalyst by filtration and the solvents by evaporation. ##STR9##
(4) A substituted pyridine salt of formula V is halogenated in a suitable protic, acidic medium such as dilute hydrochloric acid, aqueous acetic acid and the like with an appropriate halogenating agent, X--Y, in which X is as previously defined and Y is chloro, such as iodine monochloride, bromine monochloride, chlorine and the like at a temperature of 0.degree. C. to 40.degree. C., preferably at room temperature, for a period of 1 to 24 hours, preferably 8 to 18 hours. The product of Formula I wherein X and R are as previously defined is readily isolated by basicification of the reaction solution with a suitable base, preferably ammonium hydroxide, whereupon I precipitates and is subsequently collected by filtration. ##STR10##
(5) The free base of Formula I is readily converted to the acid addition salt of formula VI wherein R, X and A are as previously defined by methods well known in the art, such as by reaction of the free base with the mineral acids mentioned previously in a suitable inert solvent at or about room temperature followed by removal of the solvent or dilution with a less polar, misible solvent to afford the salt.